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- [00:03]
A
Hello and welcome to Drug Story. I'm Thomas Goetz. We'll get back to big shows about specific drugs next week, but this week we're doing a special episode, a conversation with Dr. Eric Topol, the expert cardiologist and researcher. Dr. Topol is the founder and director of the Scripps Research Translational Institute in San Diego. He's the author of the new book Superagers. It's a deep dive into the science of aging and longevity with an emphasis on science. I first Met Eric about 20 years ago, just after the Human Genome Project had successfully mapped 3 billion base pairs of DNA. The project seemed like the start of something big with a deeper understanding of our genetic code. There was so much excitement about personalized medicine, the idea that medicine would be able to treat people based on their specific genetic patterns, allowing earlier and more effective treatment. This was a huge deal. Part of the buzz was that individual drugs would be matched to individual people. Drugs would be more effective and more tolerated because of our DNA. This is called pharmacogenomics, and it was supposed to transform medicine and human health. Well, you may have already guessed where I'm going with this. Here it is 20 years later, and a lot of that excitement has fizzled. Sure, science has figured out genetic connections on many, many drugs, more than 100 of them. But a lot of those insights are still sitting on the she. Very few doctors are actually tailoring their treatments to individual patient DNA in their clinics. I wanted to talk to Dr. Topol about this disappointment about his career and how he has always put the science first. He shares the story of Vioxx, a pain reliever that he was early to see carried massive risks for people taking it. Eric put his career on the line to help the world know about those risks. When we talk about longevity and public health and tuberculosis and books and vaccines, it's a really fun and enlightening conversation. I really think that if you're enjoying drug stories so far, you'll love this episode. We'll be back next week with another regular episode. Okay, here's my conversation with Dr. Eric Topol.
- [02:19]
B
Doctor Topolk, if you can explain what pharmacogenomics is, is and try to capture that moment that we were in about 20 years ago on the heels of the Human Genome Project.
- [02:28]
C
Yeah, well, first, Thomas, call me Eric. So I don't feel so old right now. Back then, when we were just getting going with this early consumer genomics, right. 23andMe and Navigenics were a couple of the first out. We didn't realize how much more we needed to learn. So we were thinking we could predict the risk of people with various common diseases, you know, whether it's different cancers or heart disease or type 2 diabetes. But as it turned out, we only had a very limited cut of the variants in the genome that were linked to the disease of interest for predicting risk. So a lot of miscues were coming out of that. And, and I think we learned a lot because we learned that some people really did want to learn about their genomics. The problem was we didn't have really good data to work with. It took a lot more combing through the genome with hundreds and hundreds of these so called genome wide association studies in diverse ancestries too, because turned out there were very different variants, some were cosmopolitan, that worked across all, but many were unique to Asian or African or certain parts of European ancestry. So we learned a lot since then. Now polygenic risk scores should be used, they should be routine, but they aren't and it's really unfortunate. The other thing that you were getting at is what about these variants that would predict our response to drugs? And what's amazing is we still don't do that. And a perfect example that's particularly poignant, there's a skin condition called Stevens Johnson syndrome which can be fatal. One out of four people can die from it. And it's basically from specific medicines that are high risk. One of them is tegretol carbamazepine, a frequently used medicine for epilepsy and peripheral neuropathy and other indications. So what we do in this country is like Russian roulette. We give the prescription, we don't get the genomics, whereas in many other countries you cannot give the prescription until the genomic data is available. And so, you know, a colleague of mine, his wife wound up in intensive curing it as if she had third degree burn throughout all her body from the toxic skin reaction and almost die. So that happens because we don't use the data that we know. And over 150 drugs that are approved by the FDA, as you know, maybe it's even 200 by now have some type of genomic label where we'd be much smarter if we got the genomic data. Some of these are cancer drugs, some of them are, you know, all over the types of indications, but we don't do it. It's really unfortunate.
- [05:29]
B
So you brought up that list and for again kind of sticking in that era of 2010, 2015, the FDA published that list on their website of drugs with pharmacogenomic indications or attributes. And I used to scroll through it when I gave a talk because it was. To me, it was such a popular symbol of. There were dozens of drugs, as you say, like 150 drugs that had the potential to allow doctors to be better about targeting the medicine for good or for bad. Right. Use it or don't gonna work or it's gonna be dangerous or it's not gonna work at all. But I looked yesterday and that list is still there.
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C
Oh, yeah.
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B
Actually hasn't grown, though. It's. Well, now it's in three sections. So there's. I'm gonna read here, there's a 62 drugs where there's clear value to use with therapeutic recommendations, 22 drugs with potential impact, and then 40 drugs with evidence not established and. But I guess there's some hope. But. So that list hasn't changed very much. And it's certainly, as I think you were suggesting, it's certainly not worked its way into clinical practice.
- [06:41]
C
Right. And the sad part for that is, you know, someday most people will have a whole genome sequence and they'll have that data and they'll have a card in their wallet or purse. It tells them that they could have severe reaction to certain drugs or they need higher or lower doses, like, for example, you know, warfarin, the blood thinner. We could tell from the genotypes what the dose would be instead of futzing around for weeks to try to find the right dose by trial and error, just if we knew a few different genotypes. But the problem is you have to send these out now. They're very expensive. It takes like a week to get them. So practically, it's just not feasible because, you know, you want to start the medicine and you don't have that information and by the time you get it, and, you know, it's not covered by insurance, typically at all. So we've never really embraced the era of pharmacogenomics in this country. It's inevitable someday because some invaluable information there, but we haven't done it yet, and that's sad.
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B
So I guess, is this a problem with the. Is this a problem in terms of the research? Is it happening or is it.
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C
Oh, no, it's much more the practical
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B
issue in the clinic.
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C
Yeah, yeah. Because you see a patient, you're starting this drug, you know, there's a genomic story, but you can't be bothered with it because it takes too long. You know, typically, you know, in health systems, there's not, you have to other, you know, send out for. And then maybe two weeks you get the answer. I mean, you know, it's just, yeah, very impractical. And there were some exceptions where like a drug that's commonly used, Plavix, Plavix has resistance in some people, the PTY12 gene variant. And then you would go to a different drug. And so let's say you put in a stent and you, you didn't want that stent to clot. Well, there were some people that, you know, wound up with a stent clot problem just because they didn't get screened for potential resistance. And some labs or different parts of the world, not just in the US and Canada and other places, they actually developed an in lab assay. You could take a, a drop of blood and you could find out the genotype. You, you know, rapidly. But that was a rare exception to this whole story.
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B
So is there, are there education efforts? Are there, is there anybody who's trying to kind of revive this promise of pharmacogenomics in the clinic?
- [09:17]
C
Not that I know of. I mean there should be. One of the big steps was to get sequencing down to a couple hundred dollars, making it affordable. And there was a paper just this week where in Australia where they did whole genome sequencing in a large population, they found all kinds of things that was, you know, people that had high risk for a sudden death or for cancer, these certain syndromes that, you know, these so called pathogenic genes. But someday it'll be you, you'll know all your pharmacogenomic relevant interactions. We just don't, we're not geared up for it and we're not promoting it. There's no effort in this, there's no one behind this movement, unfortunately.
- [10:01]
B
Yeah, when I look at the list, like there's, I mean there's statins that have a possible genetic indication which could, as I understand it, exacerbate side effects. There's antidepressants like sertraline, very common, actually the most prescribed antidepressant, which has a high indication of genetic interaction whether it works or not. And it's just, it's staggered that that kind of opportunity to kind of optimize a treatment is just.
- [10:28]
C
Yes, I agree. It's one of these many examples of when there's this compartment or orbit of medical knowledge and then there's another huge chasm, another orbit or compartment of medical practice and they don't connect at all. And this is, you know, kind of an exemplar of that.
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B
Right. And now correct me if I'm wrong. But is oncology an exception?
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C
It's an exception, but even there it's not used as widely as it should because you would know, like, for example, drugs like 5 fluorourouracil, very commonly used chemotherapeutic drug, and many others, you would be able to predict side effects and how, you know, dose metabolism. With some of these drugs, it is used, but that's one specialty that's more leaning in that direction, but still not completely the way it should be, which is, you know, in a systematic fashion.
- [11:27]
B
Yeah, yeah. Well, so we talked about pharmacogenomics. I want to ask you, you have a great life story about the pros and cons of drugs and using drugs in somewhat naive ways to treat very common conditions and the kind of chaos that can emerge. And I think, yeah, I think you know what drug I'm talking about. But it kind of changed the course of your career when you decided to stand up and make it clear that this drug that everyone was saying was amazing, had some concerns about it. And I just wanted to ask you to tell that story a little bit.
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C
It's quite a story. I hate to go back there, but you're bringing up the Vioxx story and
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B
I'll make it relevant again.
- [12:16]
C
So many of the older listeners will remember Vioxx. In 2004, it was suddenly taken off the market by Merck. But three years to that date prior, we had published a paper in JAMA to say that this drug had serious issues with heart attacks and strokes, but particularly heart attacks that were not being acknowledged by Merck. And it was a hot, hot drug because it was far more potent than drugs like Aleve and Advil and Aspirin for pain and arthritis. So it was widely used. And so when we wrote that paper in 2001 and the front page of the Wall Street Journal, I said, this could be a public health disaster. And who would have known that three years later, they finally. It took them that long to finally take the drug off the market. The problem then was the CEO of Merck, Ray Gilmartin, at the time, he got a big press conference about why they're taking the drug off the market. And he said, we. We just now saw the signal and that really was hard to take because it was there three years ago, and they tried to destroy our publication to take. They even pressured the editor of JAMA that if she published our paper, they would sue the jama, which they never did, but they also pressured us directly. So, anyway, I didn't like that. And I wrote op ed, my first op ed ever. The New York Times, which they renamed it as a good riddance to a bad drug. Now, that was kind of strong, but the point I was trying to make was we've known about this for years and the company needs to be, you know, much more in touch with the harm that it could be inducing. Now, since that time, there's been no accountability by Merck, that is, they got off all their lawsuits, class action suits. They just appealed and appealed and appealed and they should have been indicted. The senior management who knew what was happening, they had emails that showed they knew about the heart attack problem. But that's the problem we have right now is you can market a drug, you can know about unanticipated side effects and come up with stories to try to. Their story was, oh, well, it was compared to Naproxen and Naproxen protective. Well, you know, no, that's not the story. The story was that Vioxx, now I took Vioxx, it was really very effective. I had, you know, a lot of knee arthritis, but I probably would still take it if it was at the right dose. But they were pushing the dose to get the maximum. And that's where we started to see the clotting for the heart attack syndrome. Anyway, it was a lesson that we keep seeing. Thomas.
- [15:14]
B
I mean, I remember you telling me that story 15 years ago. And I remember the first time that I really learned that like the clinical trials are not enough. We have to look at what happens to drugs in the real world.
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C
Yeah.
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B
Just last week you wrote a great essay about aspirin, which, you know, use for hundreds of years or a hundred and being used for heart disease for decades. And yet again, this is a prompt for you, but the evidence shows us that it's not as benign as we think it is.
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C
Yeah, I mean, it's almost inculcated in the public to take this low dose aspirin and then for our president to take four times as much. Against advice. But when you look at the data, as you said, that has come out since the early days of low dose aspirin being advocated, we've Learned that people 70 and older are at very high risk. So unless they already have heart disease, which was the White House gave the wrong recommendation. Anyone over 70, unless they have bona fide stent, a bypass operation, a heart attack, those are the things they shouldn't be taking because the bleeding risk is higher than the benefit. So we're always learning. And the problem Is we once something is in practice we don't often rethink it. Re, you know, interrogate it and it's really important. You worked for years with. Was it Goodrx?
- [16:45]
B
Yes, yes, I sold Goodrx and we started a nice public health economic data science there doing research. That was what started me on this. As you know, I spent 10 years in startups about prescription drugs which was not exactly intentional. And I came away with all these notions about drugs and all these kind of half baked stories about. And then I was like, okay, maybe I just use that as a way to tell these larger stories about where my true interest lies is which is public health and kind of the, what nerds call the social and commercial determinants of health.
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C
So yeah, yeah. Well you come a long way from when I first met you, Wired magazine as the key force in Wired magazine, become a prescription drug guru. So that's very interesting.
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B
Well, I like to think it's a progression. Do you have time for a couple more questions?
- [17:39]
C
Yeah, go ahead.
- [17:40]
B
Okay, good. So along these lines, one of the things I was curious about was you know, I saw you at, a month ago you were at this Wired event here in San Francisco. I was no longer on the stage, I was now in the audience. But there was a kind of typically wired enthusiasm for, for all the, I mean all the stuff that is in the vogue here. And I live in San Francisco and everybody's all abuzz about longevity again. And as you know, and as most people don't know, longevity started with public health like it was all about, it was all about sanitation and immunization and basic structures of public health. But now it's all about peptides and protocols and supplements and, and, and sales I think maybe.
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C
Yeah, sales. Sell, sell, sell.
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B
Exactly.
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C
All these longevity people, supposedly, you know, influencers with whatever expertise, some often none, they're selling and that means to me they're non credible. If you, if selling a supplement or peptides, you know any of this stuff, protein bars, I mean add those, the whole list to me, then you've lost your real credibility as a, as a scientist because you shouldn't be doing that. At the same time of your trying to unravel what is the ways to change the process of biological aging.
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B
Well, I agree with you but you having just written a number one bestseller superagers about longevity and the real science. I'm just going to ask, have people asked you to sell supplements and be their pitch fan?
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C
No, I think they got the message. I think they realized that I would Never go near that. And it's really disappointing to see some people that they've done so well in their life and they just can't, you know, do enough to profit. It's sad. But no, I think this is a real problem and you know, I can count on, you know, one hand the number of people who are active in healthspan extension and promoting this that aren't in the business of selling and they're hucksters. It's really, it hurts the feel because there's so many good things that are happening right now and in the science of aging, but unfortunately it's contaminated, if you will, from all this stuff. Yeah.
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B
So let me just ask about. Because one of the things that was to me as a public health guy, kind of gratifying to hear you on the stage at Wired. They ask you about peptides, they ask you about all these kind of very cool things on the vanguard of science. But ultimately they asked you like, what do you do? And it came down to very simple conscientious practices of just like basic prevention like, like that public health has been talking about for, for decades.
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C
That's right. The data to support those basic things has gotten so much stronger as I reviewed in Superagers. So we know what foods, what beverages, what sleep quality, all this stuff on, you know, what type of exercise and you know, we've learned so much more. And the data to support all these things, some of it through randomized trials, are huge, prospective long term follow up trials. So it's gotten so much more solid. And then we've added all these other factors I call, you know, called them lifestyle plus. But you know, things like being out in nature and you know, having social connections and purpose and all these other things that might have been thought of as softer social science, but they have really strong backing now. So. Yes, but that's not enough because Thomas, as you know, lots of people do all those things, they're religious about it and they still wind up with cancer or heart disease or Alzheimer's. That's why we need to build on lifestyle. And that's what the whole book was about, was how we can use these other layers of data, these proteins and biomarkers, genetics and exposures and on and on to use multimodal AI to then predict and prevent. And that's where we're headed. And that's what I'm really excited about. I have one last question for you. You wrote a book about tuberculosis. Yep. Okay. And I thought that was really remarkable because that was different than A lot of the other things you wrote about then this other guy wrote a book on tuberculosis.
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A
Yes.
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C
And been on the bestseller list for years. What the hell's going on there?
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B
Let me just say. So my book, I appreciate you mentioning it's called the Remedy, which is about the germ theory of disease and the history of tuberculosis and in particular the invention of Sherlock Holmes. So if you like historic, kind of true to life medical mysteries that for you, the current bestseller is by John Green, very famous author. More famous than me and more famous than both of us put together. And he wrote a very good book, an excellent book about tuberculosis in the present day. He did. He was very generous. He cited my book at length. He called it brilliant, which I'm willing to tell anyone else, but as I always say, it's better to be on the bestseller list than to be referred to.
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C
What is it about that book, besides the fact that he's so established, that made that such a. I mean, here it is years later, I don't see the public reading about tuberculosis so much. What is it that made it such a big book?
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B
Well, and not mine. Yeah, yeah, right. My book did great. Okay.
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C
But this book is like, you know, I'm still see every week I look at it.
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B
Yeah, yeah. No, I grant you, I was not number one bestseller for six months. He's a, he's a marvelous storyteller. Okay, okay. Storyteller. He has a narrative. His narrative is about a young man he met in Africa. So it's an incredible. And then. And he, he has a very strong personal relationship to this guy. I forget his name, but. But that becomes really the, the through luck book. And he also makes a amazing point in that book which comes back to our conversation and comes back to the drug story podcast, which is. It is a third that any. For any condition, including tuberculosis. But for any condition that exists right now where we have an effective treatment that is tantamount to a cure, it is absurd that anybody in the world should go without that cure. And that is the case with regulosis still, that we have cures on hand that are not getting to the people. And he made that argument. I did not.
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C
Yeah, well, I'm all for that and I'm going to go on in the future. Say we have preventions that we're not using to prevent dreaded diseases. The main three age related diseases. But I guess what you're. What you've told me that I, I get out of that is the Michael Lewis storytelling talent helps a lot.
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B
Yeah. Well, again I consider myself a very gifted storyteller. Okay. But yeah, you know, he's, he's a machine. He's a force.
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C
When anybody writes a book about tuberculosis, particularly, you know, in the United States or someplace in a high income country, you don't usually see it, you know, become this big.
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B
Let's say he's the Beatles and I'm the. So I have my audience. But it's,
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C
I would just go back and say you brought up the Vioxx thing. It's something I try not to think about because it was such a tough time in my life. But one thing I'd say is it isn't right that these companies, like the opioid companies, Purdue Pharma, the Sackler family and many of the others that have gotten away with this stuff and it isn't right that they're somehow immune their senior management and makes these decisions that they knowingly hurt people that should not be accepted by our. And to be able to, like for example, Purdue Pharma and all these other drugs where they go ahead and they do settlements, you know, that mostly go to the lawyers and not the injured people and that. But what about these people that are in control of marketing drugs and knowing they're harmful? That, that still, it eats me inside that we allow that and until something happens, this will continue. And you know, that was a story that's 20 some years old. All right, that Vioxx. And there's been several more since then and there will be more until we get some teeth into this.
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B
Yeah, no, and I, I grant you all that. And I agree, I am always careful to say, because everyone asks me, are you anti pharma? And I'm, I'm very clear. I'm, I'm not anti Pharma. If we have drugs that work and help people, that is a good thing. I think some of the structures that we've created, like the patent system, like the Pharma companies pricing drugs without any kind of government negotiation. Some of these mechanisms are easily or are readily exploited by companies to maximize profits and to maximize usage. And unfortunately, sometimes patient harm is an allowable risk. There is a moral line there that I think, you know, unfortunately, it's not a legal line, it's a moral line.
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C
Sure, sure. No, and I, I accept that. You know, we have some real incredible progress that's been made by Biopharma. Right. I mean, no question. I'm going to put out tonight the, another substack on the shingles vaccine, which is doing things that just, you know, slowing aging and, you know, preventing the Alzheimer's disease. I mean, you know, that came out of pharma. These are great contributions. You mentioned the glp, one whole family of drugs which is going to get built. A lot of people think that we've reached some kind of early plateau and there's 10 more of these gut hormone mimetics and things to build on. Triple receptors, quadruple receptors. These are really extraordinary. It's just the lack of liability, the lack of accountability, that's the only thing that concerns me. But otherwise, I'm with you. Anyway, thank you for your conversation and I'll be tuning in.
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B
Thanks for wearing the gingham.
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C
Take care, Thomas.
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A
Okay, that's it for this bonus episode of Drug Story. Drug Story was created, written and hosted by me, Thomas Goetz. Molly Warner is our research director. From Reasonable Volume. Rachel Swaby produced and sound designed this episode. Mark Busch is our Engineer. Thanks to Dr. Eric Topol. You can find his substack@erictopol substack.com and Drug Story is an independent production. If you would like to support our work, contact us at Drugstore Co. You can also subscribe to our substack there and be notified when new episodes come out. Listening to this episode of Drug Story might cause you to get vaccinated. Take a DNA test and ask your doctor if you should really be taking low dose aspirin. We recommend that you avoid longevity hucksters. Trust nature as well as nurture and read the remedy. It's an amazing book about the germ theory of disease and tuberculosis.
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C
Sa.